Idialkelicarb amyl pieekazines



Patented Apr. 19, 1949 am-m nor) OFBREPARINGIIMONOAIJKYDAND :BIALKYLsflARBAMYL PIBERAZINES:

= Samuel Kushner, .N-anuet, and LouissBrancone, "iil'earlilt ven N; Y., assignors to American ""QyanamidiCompany, New YorkrN. Y. a .cor-

The present invention relates to new organic compounds and "their preparation. More particularly, it relates to substitutedzacarbamyl piperazines and to methods of preparing the same.

film-our co-pending.rapplioat-ion-; SerialtNumber highly effective in the treatment of filariasis and in veterinary practice in the treatmentor ascarides in'animalssuch as the -dogi They exhibit t is. preie redc ia alkyl;,si .e zine .ratherithana drat thereofiibe us a 's rt n material and that a sufficient eXcessbe'usedito provide an acceptor iorhy drochloric acidformed during reaction.

The reaction 152118311111 carried: out in; solution. Temperaturesof 2 0,?to 100 C are usually sufe ent toaccomplishithe reactionsin a reasonabl time. ,qeneral-ly about; 309'to5 "C. Willlhe employjed w ens aqueous l al ohol. s ..use. 1.as. th so nt,,.wh e "somewhat-hi her temp r tures are desirablejorsthe hon-:aqueous p solvents. At temperatures. below this level the r actionmay "h t o. slow, nd vtemperat es above'th s level (serv napartieulariu e ulp rpos Substantianyany arbamylfhalid e ftheim low toxicity and arenvery effective in relatively g' small doses. Noox We have nomioundtin theipresent application,

that compounds having-the general formula:

wherein Alk'; and -R-:have'the:valuesinotedtabove Mk; .jj --and.' X is halogen, may lee-used; suchasa for R example mono-methyl, .mono-ethyl,monoepro- "y" -pyl,dimethyl, diethyl,-di-isopropyl,\dienapropyl,

R methyl ethylcarbamyl halides and thedike. .The

in which R is hydrogen or a lower alkyl radical andAlk. is."aslowenalkylma ieali ,arejn g neral highly active as filaricides. As usedgherfiinsthe term lower alkyl nradical means a radical of one to four carbon atoms. The invention is also concerned withrsalts ofiethese compounds, both addition salts, suchmasthe hydrochloride, sulfate, citrate and the like, and quaternary salts such as the.,me hocl loride, m thiod de ethobrom de, a

benzochlorideiand heglike.

In eneral; l h compounds. of hep eeent vention.aremco orless; sina eir llowuoils soluble tuteido nt he nitro en by ne r wo a l ero ps- A'sv a st ingamat f"Q:suh tut .a yl mp razine..suchasg112 5?trimethx pinerazine;1 dimethylpiperazine; 132,6 '-'tri1nethy lpiperazine; 2 6 methy pinerazine; V 305 r. neth piperazine, etc., maybe used, either 'in anhydrous form or as a hydrate such as 2,5-dimethyl piperazine hexahydrate. In carrying out the present invention it is, preferred flthat non-aqueous solvents including benzena toluene, chloroform, car.

bon tetrachloride dibutyl ether. and the like be:

:reactions using diethylcarbamyl halides, .suchias the chloride may be-taken' asuillustrative since the reaction is typical. The invention, however, is not so limited. Although any halogen may be used the chloride-- and. bromide are: the most practical.

When the, reaction is.. carrie d :out in, anaqueous l o l 1s c as1 h ut -%vthen rth u eacted tartinaalky iper zin i-is u e o pr cipitate '1 after; the reaction,by acidificationwoisthe, mediu with an acid suchras hydrochloric acid. After this is removed, by filtration,- essentially only :the =monoand di:carbamylalkylpip-erazines remain a in the aqueous alcoholicxfiltrate. Concentration of ,this,filtrate by distillation followed by removal of the :laststracesof vwaterstltildq g ,wazeotrfllic distillation with benzene, a toluene, or the-s like leaves the mono-carbamylalkylpiperazine in suspension as its insoluble .hydrochloride while the di-carbamyalkylpiperazine remains in solution. Theformerin the form of its salt'is then readily obtained. in nearly ap ure state by filtration. The latter may be recoveredfromthe filtrate -on,c,oncentrationby. distillation: or evaporationand coolina Alkylation: of the isolated mono carbarnylalkylrpin razinesemayl arr ed ou y h usu procedure or;el ylatineis ondaryin s. \In ene al; lley-I st ller-tee,- alkyl sulfonatesn-and alkyl halidesmayah he. used as alkylatirig-agen ts, with the possible exception of alkyl iodides which tend to form quaternary salts. In the specific case of methylation, rather than the use if the above alkylating agents, a preferable method is a reductive methylation using formaldehyde in formic acid or formaldehyde in hydrochloric acid in the presence of zinc dust.

The process of the present invention will be more fully illustrated in conjunction with the folowing examples in which the process is to be taken as illustrative only and not by way of limitation. All parts are by weight unless otherwise noted.

As was pointed out above, it is not necessary to utilize an aqueous solvent. This is illustrated in the following example. In fact, non-aqueous solvents are preferable in acylating C-alkyl substituted piperazines. In using non-aqueous solvents, the piperazine, rather than a hydrate thereof, should be the preferable starting material. A sufficient excess should be used to provide an acceptor for hydrochloric acid formed during reaction.

In 400 parts of dry benzene, 114 parts of anhydrous 2,5-dimethylpiperazine is dissolved at 65 C.. To this is added dropwise 67.8 parts of diethylcarbamyl chloride with the temperature being kept at 65-70 C. The reaction mixture is stirred at 70 C. for one-hour and then is heated under reflux for six hours. The reaction mixture is cooled to 15-20 C., 120 parts of ethanol is added, and it is made acidic by addition of concentrated hydrochloric acid. The unreacted 2,5- dimethylpiperazine precipitates as its dihydrochloride and is removed by filtration. The filtrate is concentrated to a syrupy residue. This residue is cooled, made strongly basic with 50% sodium hydroxide solution, and the oil which separates is dissolved in diethyl ether. After drying the ether solution over solid potassium hydroxide, the solvent is removed by distilaltion; and the residue is distilled under diminished pressure to give 1- diethylcarbamyl-2,5-dimethylpiperazine having a boiling point of 105-107 C. at 1.5 mm.

EXAMPLE 2 1 -diethylcarbamyl-2,5 -di1nethylpiperazine hydrochloride By following the procedure of Example 1 and acidifying the reaction mixture with hydrochloric acid, crude 1-diethylcarbamyl-2,5-dimethylpiperazine hydrochloride is obtained. Liberation of 1-diethylcarbamyl-2,5-dimethylpiperazine from this crude hydrochloride by treatment with 50% sodium hydroxide, extraction of the oily base with ether, drying the ether and removing the solvent by distillation, and finally distilling under diminished pressure gives pure l-diethylcarbamyl-2,5-dimethylpiperazine.

EXAMPLE 3 1 -diethylcarbamyl-2,4,3-trimethylpiperazine 91 parts of 1-diethy1carbamyl-2,5-dimethylpiperazine is dissolved in 65 parts of 90% formic acid. Then 53 parts of 36% aqueous formaldehyde is added dropwise at 75 C. over a period of fifteen minutes. The mixture is refluxed at 105-110 C. for two hours. The excess formic acid is removed by distillation until the temperature of the residue rises to about 150 C. After the distillation of the formic acid, the residue is carbonate. The product is then extracted with chloroform, dried, and after removal of the chloroform, distilled.

We claim: 1. Compounds having the general formula:

Alk. Alk.

\NOCN/ tr N-R in which R is a member of the group consisting of hydrogen and lower alkyl radicals and Alk. is a lower alkyl radical, and salts thereof.

2. Compounds having the general formula:

in which Alk. is a lower alkyl radical, and salts thereof.

3. Compounds having the general formula:

Alk.

Alk.

is. i

Alk.

in which Alk. is a lower alkyl radical.

4. 1-diethylcarbamyl-2,5-dimethylpiperazine. 5. l-diethylcarbamyl 2,4,5 -trimethylpiperazine.

6. l-dimethylcarbamyl 2,4,5 trimethylpiperazine.

7. A method of preparing compounds having the formula:

Alk.

in which R is a member of the group consisting of hydrogen and lower alkyl radicals and Alk. is a lower alkyl radical which comprises mixing together and allowing to react a compound having the formula:

Alk.

in which R and Alk. are as defined above and a member of the group consisting of monoalkylcarbamyl halides and dialkylcarbamyl halides in a solvent.

8. A method of preparing compounds having the formula:

Alk. Alk.

NocN 1'1 N-H a i in which Alk. is a lower alkyl radical which comprises mixing together and allowing to react a compound having the formula:

Alk.

I liN A N H Alk., in which Alk. is as defined above and a dialkyl carbamyl halide in a solvent.

9. A method of preparing compounds having the formula:

Alk. Al\k. l

l NOON H N-Alk. A k.

Alk.

in which Alk. is lower alkyl which comprises mixing together and allowing to react a compound having the formula:

Alk.

No references cited. 

